1. Field of the Invention:
The invention herein relates to medical treatments of cholesterol calculi (particularly gallstones) by contact dissolution with organic solvents. More particularly it relates to therapeutic methods using low viscosity non-toxic pumpable solvents.
2. Background of the Prior Art:
The contact dissolution of cholesterol gallstones by organic solvents in human patients is a well recognized medical procedure and may be favored over surgical procedures to remove gallstones in patients at increased risk of surgery; see, for instance, U.S. Pat. No. 4,205,086. The dissolution procedures normally involve infusion of the solvent into the biliary tract (including the gallbladder and the bile ducts) by means of a T-tube, nasobiliary tube, percutaneous transhepatic catheter or cholecystostomy tube by use of a constant infusion pump or by gravity or by manual repeated installation and withdrawal using a syringe; see Palmer, et al., Gut, 27, 2, 196 (1986). Often the stones fragment during the dissolution procedure, which advantageously increases the rate of dissolution.
A number of different types of solvents have been used or suggested for the dissolution procedure. These include organic solvents such as diethyl ether, chloroform or d-limonene as well as aqueous micellar solutions of bile salts. The aforementioned U.S. Pat. No. 4,205,086 also lists a large number of useful liquid fatty acids and the alcohol esters thereof. A further solvent which has received substantial attention is monooctanoin, mentioned in U.S. Pat. No. 4,755,167 and several articles, such as Thistle, et al., Gastroenterology 78, 5, 1016 (1980). More recently a C.sub.5 ether, methyl t-butyl ether (MTBE) has been used as a cholesterol gallstone solvent; see, e.g., Allen, et al., Gastroenterology, 88, 1, 122 (1985); Thistle, et al., U.S. Pat. No. 4,758,596; and Thistle, et al., N. Engl. J. Med., 320, 633 (1989).
While all of these materials have shown some efficacy in in vivo and/or in vitro tests, all have some undesirable side effects or physical properties. Monooctanoin, for instance, has a relatively high viscosity and dissolves gallstones very slowly. MTBE was selected by Thistle,, et al., because its boiling point is above body temperature, and is currently the solvent most often considered to have the best potential for contact cholesterol gallstone dissolution. However, it is known to have definite side effects, including nausea and vomiting, which it is believed are caused by increased levels of MTBE in the blood; see Esch et al., Gastroenterology, 100, 4315 (1991). Further, if MTBE escapes from the gallbladder into the small intestine, it causes signs of systemic toxicity (sedation), pain and by endoscopy, damage to the epithelium of the small intestine. Entry of MTBE into the blood stream causes hemolysis, and one case of renal failure (reversible) has been reported. MTBE also has a relatively low boiling point (55.degree. C.), not far above ordinary body temperature, which poses some volatility problems in use because of its low flash point and strong, unpleasant odor. Those materials such as diethyl ether which have boiling points below body temperature are hazardous for clinical use because of rapid volatilization and marked increase in volume in use.
While as noted prior art has generally indicated that cholesterol gallstones can be dissolved using esters in the C.sub.2 -C.sub.20 range [see the aforesaid U.S. Pat. No. 4,205,086 and Flynn et al., J. Pharm. Sci., 68, 9, 1090 (1979)], such treatments as described were taught to be unduly slow, requiring on the order of several days. It is normally unacceptable to perfuse a patient for such an extended period; not only is the risk to the patient high for a prolonged period, but in addition it is likely that the patient's normal movements during that time, even though restricted, may be sufficient to impair the perfusion. Neither of these references has taught any focus on the C.sub.5 -C.sub.6 esters are being free of problems such as slow dissolution rates or concentration of solvent in the blood stream.
Recently there has been developed a novel infusion pump which produces a high flow rate at low pressure. This pump has been described and claimed in U.S. Pat. No. 4,902,276, issued Feb. 20, 1990, and U.S. patent application Ser. No. 07/482,194 (Feb. 20, 1990) by S. Zakko (the "Zakko pump"). While this pump has proved very affective for gallstone dissolution, its satisfactory performance depends on being used with relatively low viscosity solvents.
It would therefore be advantageous to have a therapeutic procedure available in which cholesterol gallstones could be easily, safely and rapidly dissolved by a solvent which would be effective for dissolution of cholesterol gallstones, free of a tendency to accumulate in the blood stream, easy and safe to handle for medical personnel and capable of being used in the most effective equipment such as the Zakko pump.